Trans-1-p-(dialkylaminoalkyl) phenyl-1 2-diphenyl-alk-1-enes and salts thereof

ABSTRACT

A TRANS ISOMER OF AN ALKENE DERIVATIVE SELECTED FROM THE GROUP CONSISTING OF COMPOUNDS OF THE FORMULA:   1-(R1-N(-R2)-A-),4-(R5-C(-R4)=C(-R3)-)BENZENE   WHEREIN R1 AND R2 ARE ALKYL OF 1-2 CARBON ATOMS, A IS ALKYLENE OF UP TO 4 CARBON ATOMS, R3 AND R4 ARE SELECTED FROM THE GROUP CONSISTING OF PHENYL, HALOPHENY, METHYLPHENYL AND METHOXPHENYL, AND R5 IS ALKYL OF 1-4 CARBON ATOMS, AND COMPOUNDS OF THE FORMULA:   (R5-C(-R4)=C(-R3)-)PHENYL)-A-N&lt;   WHEREIN -N&lt; IS SELECTED FROM THE GROUP CONSISTING OF N-PIPERIDINO, NMORPHOLINO AND N-PYRROLIDINO, AND A,R3,R4 AND R5 HAVE THE MEANINGS STATED ABOVE, AND THE PHARMACEUTICALLYACCEPTABLE SALTS THEREOF SAID COMPOUNDS EXHIBIT OESTROGENIC AND ANTIOESTROGENIC ACTIVITY.

United States Patent 3,637,856 TRANS-1-p-(DIALKYLAMINOALKYL) PHENYL-1,2- DlPHENYL-ALK-l-ENES AND SALTS THEREOF Justus Kenneth Landquist and Dora Nellie Richardson, Macclesfield, England, assignors to Imperial Chemical Industries Limited, London, England No Drawing. Filed June 22, 1966, Ser. No. 559,409 Claims priority, application Great Britain, July 12, 1965, 29,436/ 65 Int. Cl. C07c 87/28 US. Cl. 260-570 R 11 Claims ABSTRACT OF THE DISCLOSURE A trans isomer of an alkene derivative selected from the group consisting of compounds of the formula:

wherein R and R are alkyl of 1-2 carbon atoms, A is alkylene of up to 4 carbon atoms, R and R are selected from the group consisting of phenyl, halophenyl, methyl phenyl and methoxyphenyl, and R is alkyl of 1-4 carbon atoms, and compounds of the formula:

wherein This invention relates to alkene derivatives which have valuable therapeutic properties.

According to the invention we provide alkene derivatives of the formula:

wherein the R R NA group is in the mor p-position relative to the CR =CR R groups, wherein R and R which may be the same or different, stand for alkyl radicals of not more than 6 carbon atoms, or the --NR R group stands for a nitrogen-containing heterocyclic radical, A stands for an alkylene radical, R and R which may be the same or different, stand for aryl radicals, optionally substituted by one or more radicals selected from halogen atoms, and alkyl and alkoxy radicals, and R stands for an alkyl or aralkyl radical, and the pharmaceutically-acceptable salts thereof.

It is to be understood that the above definition encompasses both types of geometric isomers of the compounds in question, that is, both cis and trans isomers, and mixtures thereof.

It is also to be understood that in this specification the term trans isomer means the compound of the formula:

wherein the R R N-A group is in the mor p-position relative to the --CR =CR R group and wherein R R R R R and A have the meanings stated above, wherein the aryl radicals R and R are in the trans relationship to each other across the olefinic bond. Similarly, the term cis isomer means the compound of the formula:

wherein the R R N-A group is in the mor p-position relative to the -CR =CR R group and wherein R R R R R and A have the meanings stated above, wherein the aryl radicals R and R are in a cis relationship to each other across the olefinic bond.

As a suitable value for R or R there may be mentioned, for example the methyl or ethyl radical, and as a suitable value for the NR R group there may be mentioned, for example, a nitrogen-containing heterocyclic radical of not more than 6 ring atoms, for example the N-piperidino, N-morpholino or N-pyrrolidino radical.

As a suitable value for A there may be mentioned, for example, a straightor branched-chain alkylene radical containing not more than 10 carbon atoms, particularly a straightor branched-chain alkylene radical of not more than 5 carbon atoms, for example the methylene (CH ethylene (-CH CH propylene or, 1,1-dimethylethylene 0H (ma) H, radical.

As a suitable value for R and R there may be mentioned, for example, the phenyl radical, optionally substituted by one or more radicals selected from alkyl and alkoxy radicals of not more than 6 carbon atoms, for example the methyl, ethyl and methoxy radicals, and halogen atoms, for example chlorine and bromine atoms.

As a suitable value for R there may be mentioned, for example, an alkyl or aralkyl radical of not more than 12 carbon atoms, particularly an alkyl radical of not more than 4 carbon atoms, or an aralkyl radical of not more than 9 carbon atoms, for example the methyl, ethyl, n-propyl, isopropyl or benzyl radical.

Specific alkene derivatives of the invention are, for example, a mixture of the cis and trans isomers of 1-rnethylene,

1-p- Z-dimethylaminoethyl) phenyll ,2-diphenylbutl-ene,

1-p-(Z-dimethylaminoethyl)phenyl-l-p-methoxyphenyl-2phenylbutl-ene,

l-p-(Z-piperidinoethyl)phenyl- 1,2-diphenylbut-1-ene,

l-p- (Z-dimethylaminoethyl) phenyl-2-phenyl-1-ptolylbutl-ene,

l-p- 2- dimethylaminoethyl phenyl-2-p-chlorophenyl- 1- phenylbut-l-ene,

1-p-(Z-dimethylaminoethyl)phenyl-1,2-di-p-chlorophenylbutl-ene,

1 -p- Z-dimethylaminoethyl) phenyl-1 -p-tolyl-2-pchlorophenylbutl-ene,

1-p-(Z-dimethylaminoethyl)phenyl-1,2-dip-tolylbutl-ene,

1-m-(3-dimethylaminopropyl)phenyl-1,2-diphenylbutl-ene,

3 l-p-(3-dimethylaminopropyl phenyl-1,2-diphenylbut-l-ene, 1-p-(S-diethylaminopropyl)phenyl-1,Z-diphenylbut-l-ene, or of l-p-(S-diethylaminopropyl)phenyl-1,2-diphenylprop-l-ene, and the corresponding trans isomers thereof, and 1-p-piperidinoethylphenyl-cis-1,Z-diphenylbut-l-ene, l-p-(Z-dimethylaminoethyl)phenyl-cis-2p-chlorophenyll-phenylbut-l-ene, and 1-p- 3-dimethylaminopropyl phenyl-cisl ,Z-diphenylbut-l-ene,

and the pharmaceutically-acceptable salts of all the above named alkene derivatives.

As suitable salts of the alkene derivatives of the invention there may be mentioned, for example, acid-addition salts, for example salts with an inorganic acid, for example hydrochloric, sulphuric or phosphoric acid, or salts with an organic acid, for example acetic, tartaric, oxalic or citric acid.

According to a further feature of the invention 'we provide a process for the manufacture of the alkene derivatives of the invention which comprises the dehydration of an alkanol derivative of the formula:

l i k mcnaon .oun n wherein the R R NA group is in the mor p-position relative to the CR (OH).CHR*R group and wherein R R R R, R and A have the meanings stated above, or a salt thereof, whereafter, if a substantially pure cis or a substantially pure trans isomer is required, the mixture of isomers, or of the salts thereof, so formed is separated.

The dehydration may be effected by the interaction of the alkanol derivative with an acid catalyst, for example with an inorganic acid, for example hydrochloric, hydrobromic or phosphoric acid, or with formic acid. The interaction may be carried out in an inert diluent or solvent, for example ethanol, and it may be accelerated or completed by the application of heat.

The separation may be carried out by methods known to the art for the separation of mixtures of cis and trans isomers, for example by fractional crystallsation or by chromatography. The fractional crystallisation of the mixed isomers in the free base form may be carried out by the use of an organic solvent, for example petroleum ether. The fractional crystallisation of the mixed isomers in the form of a salt thereof, for example the hydrochloride, may be carried out by the use of a relatively polar organic solvent, for example ethanol, isopropanol, ethyl acetate or acetone.

The alkanol derivatives used as starting materials in the above process may be obtained by the interaction of an organometallic compound of the formula:

RURA -Am wherein the R R NA group is in the mor p-position relative to the X group, wherein R R and A have the meanings stated above, and wherein X stands for the lithium atom or for a radical of the formula -MgY, wherein Y stands for a halogen atom, for example the chlorine or bromine atom, with a carbonyl compound of the formula R .CO.CHR R wherein R R and R have the meanings stated above. The above interaction involving an organometallic compound may be carried out in an inert diluent or solvent, for example tetrahydrofuran or ether, and it may be accelerated or completed by the application of heat.

The organo-metallic compounds may be obtained from the corresponding halogeno compounds by conventional means, and the carbonyl compounds may be obtained by alkylation of the corresponding desoxybenzoin derivatives by conventional means.

When tested in laboratory animals, the alkene derivatives of this invention exhibit oestrogenic and anti-oestrogenic activity, and they are also capable of preventing implantation of the fertilised ovum when administered at doses substantially less than those required to produce oestrogenic effects. Consequently, the alkene derivatives of the invention are expected to be useful for the modification of the reproductive endocrine status in man and animals, for example the control of precocious puberty or the management of certain aberrations of the menstrual cycle. The geometric isomers are not equivalent in their biological properties, and the trans isomers are preferred for uses in which an anti-oestrogenic effect is desired.

According to a further feature of the invention, therefore, we provide pharmaceutical and veterinary compositions which comprise at least one of the alkene derivatives of the invention and a non-toxic, pharmaceutically-acceptable, inert diluent or carrier therefor.

The pharmaceutical and veterinary compositions of the invention may be in a form suitable for oral or parenteral use. Compositions suitable for oral use may be, for example, in the form of tablets, capsules, solutions or suspensions in aqueous media or in non-toxic organic liquid media, dispersible powders suitable for the preparation of liquid suspensions, mixtures with animal foodstuffs, or premixes suitable for addition to animal foodstuffs. The said premixes preferably contain between 1% and 10% by weight of active ingredient, and the said mixtures with animal foodstuffs preferably contain between 0.001% and 0.1% by weight of active ingredient. Compositions suitable for parenteral use may be, for example, in the form of sterile solutions or suspensions in aqueous media or in non-toxic organic liquid media, or sterile dispersible powders suitable for the preparation of sterile liquid suspensions.

The said pharmaceutical and veterinary compositions may contain excipients known to the art to be useful in the preparation of such compositions, for example wetting, dispersing, suspending, lubricating, sweetening, flavouring and/or colouring agents.

The oral compositions may be in the form of tablets wherein the inert diluent or carrier is, for example, maize starch, lactose or alginic acid. There may also be present one or more wetting agents, for example an alkali metal salt of a sulphonated dialkylnaphthalene, for example the sodium salt of sulphonated diisopropylnaphthalene, and one or more lubricating agents, for example magnesium stearate. The said tablets may contain between 1 mg. and 500 mg, of active ingredient. Alternatively, the oral compositions may be in the form of gelatin capsules containing the active ingredient only or in the form of gelatin capsules containing the active ingredient in admixture with an inert diluent, for example lactose or soribtol.

Depending upon the clinical effect intended, the dose in humans is likely to be between 5 mg. and 100 mg. per day.

It is to be understood that the nomenclature for desoxybenzoin derivatives used in the following examples in this specification is based upon the followingnumbering of the desoxybenzoin nucleus:

The invention is illustrated but not limited by the following examples in which the parts are by weight:

EXAMPLE 1 A solution of 6 parts of l-p-(2-dimcthylaminoethyl) plienyl-l,Z-diphenylbutan-l-ol in 50 parts of ethanol is acidified to pH 2 with concentrated hydrochloric acid. The mixture is heated under reflux for 16 hours, and the solvent is then evaporated under reduced pressure. The residue is dissolved in 50 parts of hot water, and the solution is made strongly alkaline with aqueous sodium hydroxide solution. The mixture is cooled and extracted twice, each time with 50 parts of ether. The combined ethereal extracts are dried, and the dried solution is treated with an excess of ethereal hydrogen chloride solution. The mixture is filtered, and the solid product is crystallised from a small volume of ethanol with cooling. There is thus obtained a mixture of the hydrochlorides of the cis and trans isomers of l-p-(Z-dimethylaminoethyl)phenyl-1,2 diphenyl-but-l-ene, M.P. 196- 198 C.

1-p-(2 dimethylaminoethyl)phenyl 1,2 diphenylbutan-l-ol may be obtained as follows:

A solution of 25 parts of sodium nitrite in 100 parts of water is added slowly to a stirred solution of 112 parts of p-(Z-dimethylaminoethyl)aniline dihydrobromide in a mixture of 100 parts of water and 120 parts of 48% aqueous hydrobromic acid at 5 C., until an excess of nitrous acid can be detected by starch iodide paper. The diazonium solution thus obtained is added to a solution of 35 parts of cuprous bromide in 150 parts of 48% aqueous hydrobromic acid, and the mixture is heated at 90-100 C. for 1 hour. The reaction mixture is allowed to cool, and is then made strongly alkaline with aqueous sodium hydroxide solution. The mixture is extracted with ether, and the extract dried and evaporated. The residue is distilled. There is thus obtained N, N-dimethyl-Z-(p-bromophenyl) ethylamine, B.P. 122-1'24 C./ 11 mm,

22.8 parts of N,N-dimethyl-2-(p-bromophenyl)ethylamine and 100 parts of dry tetrahydrofuran are added gradually to 2.4 parts of magnesium turnings. The formation of the Grignard reagent is facilitated by heating and stirring. When all the magnesium has dissolved, the hot solution is treated with a solution of 12.2 parts of w ethyldesoxybenzoin in 60 parts of tetrahydrofuran. The mixture is stirred and heated under reflux for 3 hours, cooled in ice Water, and treated cautiously with saturated aqueous ammonium chloride solution until the precipitated magnesium hydroxide redissolves. The organic layer is separated and the tetrahydrofuran is removed by distillation under reduced pressure. The residue is dissolved in 300 parts of ether and the solution is extracted with 300 parts of ice-cold dilute aqueous hydrochloric acid. The acid extract is immediately made alkaline with sodium hydroxide solution, and the mixture is extracted with 500 parts of benzene. The benzene is evaporated, and the residue is crystallised from ethanol. There is thus obtained l-p-(Z-dimethylaminoethyl)phenyl-1,2-diphenylbutan-1-ol, M.P. 134-135 0.

EXAMPLE 2 The process described in Example 1 is repeated except that the Grignard reagent prepared from 22.8 parts of N,N-dimethyl-2(p-bromophenyl)ethylamine, is treated with 12.7 parts of 4-methoxy-a-ethyldesoxybenzoin, and the resulting 1 p (Z-dimethylaminoethyl)-phenyl-l-pmethoxyphenyl-2-phenylbutan-l-ol is obtained as a syrup and used in the final stage Without further purification. There is thus obtained a mixture of the hydrochlorides of the cis and trans isomers of l-p-(Z-dimethylaminoethyl) phenyl-1-p-methoxyphenyl-2-phenylbut-l-ene, M.P. 190 C.

EXAMPLE 3 A mixture of 13.4 parts of 1-p-piperidinoethylphenyl- 1,2-diphenylbutan-1-ol, 120 parts of ethanol and parts of 10 N-aqueous hydrochloric acid is heated under reflux for 3 hours. The solution is evaporated to dryness under reduced pressure and the residue is stirred with water. 10 N-aqueous sodium hydroxide solution is added and the mixture is extracted with chloroform. The extract is washed with water and dried over sodium sulphate. The chloroform is evaporated, and the residue is crystallised first from aqueous ethanol, then from methanol and finally from petroleum ether (B.P. 4060 C.). There is thus obtained 1-p-piperidinoethylphenyl-cis-1,2-diphenylbut-l-ene, M.P. 102-104 C. From the methanol liquors there is obtained 1-p-piperidinoethylphenyltrans-l,2-diphenylbut-l-ene, which has M.P. 8688 C. after crystallisation from petroleum ether (B.P. 4060 C.).

The 1-p-piperidinoethylphenyl-1,2-diphenylbutan-l ol used as starting material may be prepared as follows:

A solution of 34.0 parts of piperidine in 150 parts of benzene is added dropwise over 30 minutes to 40.5 parts of p-bromophenylacetyl chloride which are stirred and cooled in an ice-water bath. The mixture is stirred for a further 30 minutes, and the benzene is then evaporated. The residue is stirred with water and the mixture is extracted with ether. The ethereal extract is dried and evaporated. The residue is crystallised from petroleum ether (B.P. -100 C.) and there is thus obtained N-(p-bromophenylacetyl)piperidine, M.P. 98l00 C. A solution. of 26.6 parts of N-(p-bromophenylacetyl)piperidine in 700 parts of dry ether is added dropwise over 20 minutes to a stirred suspension of 8.3 parts of lithium aluminium hydride in 1500 parts of dry ether. The mixture is stirred and heated under reflux for 18 hours, and 11 parts of ethyl acetate and 100 parts of Water are then cautiously added. The ethereal phase is separated and extracted three times, each time with 100 parts of 2 N-aqueous hydrochloric acid. The combined acidic extracts are made strongly alkaline with aqueous sodium hydroxide solution and the mixture is extracted with ether. The ethereal extract is dried and evaporated, and there is thus obtained N-2-(p-bromophenyl)ethylpiperidine, which is used without further purification.

A solution of 25.6 parts of N-Z-(p-bromophenyl)ethylpiperidine in 50 parts of dry tetrahydrofuran is added dropwise to a stirred suspension of 2.28 parts of magnesium in 50 parts of dry tetrahydrofuran. The mixture is stirred and heated under reflux for two hours, and a solution of 10.6 parts of a-ethyldesoxybenzoin in 50 parts of tetrahydrofuran is then added. The mixture is cooled to 10 C. and decomposed by the addition of a solution of 60 parts of ammonium chloride in 150 parts of water. The organic layer is separated, and the aqueous layer is extracted three times, each time with 100 parts of ether. The combined organic layer and extracts are dried and evaporated. The residue is crystallised from petroleum ether (B.P. 100-120 C.) and there is thus obtained l-ppiperidinoethylphenyl-1,2-diphenylbutan-l-ol, M.P. 114- 115 C.

EXAMPLE 4 A solution of 9 parts of l-p-(Z-dimethylaminoethyl) phenyl-2-phenyl-l-p-tolylbutan-l-ol in a mixture of 400 parts of ethanol and 50 parts of concentrated hydrochloric acid is heated under reflux for 24 hours, and the solvent is then evaporated under reduced pressure. The residue is dissolved in 500 parts of water, and the solution is made alkaline with sodium hydroxide solution. The alkaline solution is extracted three times, each time with 200 parts of ether. The extracts are combined, dried and evaporated. There is thus obtained crude l-p-(Z-dimethylaminoethyl) phenyl-2-phenyl-l-p-tolylbut-l-ene as a syrup containing roughly equal parts of cis and trans isomers. 4.5 parts of this crude mixture are dissolved in 100 parts of ether, and the solution is treated with a solution of 2 parts of oxalic acid in a mixture of parts of ether and 50 parts of acetone. The precipitated solid is filtered ofi and recrystallised repeatedly from ethanol. There is thus obtained l-p-(Z-dimethylaminoethyl)phenyl-trans-Z-phenyll-p-tolylbut-l-ene oxalate, M.P. 186l88 C.

The l-p-(Z-dimethylaminoethyl)phenyl-Z-phenyl 1 ptolylbutan-l-ol, M.P. 128130 C., used as starting material may be obtained by repeating the process described in Example 1 for the preparation of 1-p-(2-dimethylaminoethyl)phenyl-1,2-diphenylbutan-1-ol except that the a-ethyldesoxybenzoin is replaced by a-ethyl-4-methyldesoxybenzoin.

In a similar manner, by replacing the m-ethyl-4-methyldesoxybenzoin by 4'-chloro-a-ethyl desoxybenzoin, there is obtained a mixture of the cis and trans isomers of l-p- (Z-dimethylaminoethyl)phenyl-Z-p-chlorophenyl-1 phenylbut-l-ene which by crystallisation of the hydrochlorides from isopropanol there is obtained the trans isomer as its hydrochloride, M.P. 256 C. From the mother liquors. by conversion of the hydrochloride into free base and then into its oxalate, there is obtained the corresponding cis isomer as its oxalate, M.P. 186188 C.

The 4 chloro-a-ethyldesoxybenzoin is obtained as follows:

11.3 parts of 4'-chlorodesoxybenzoin are dissolved in a solution of 1.13 parts of sodium in 160 parts of ethanol, and 7.7 parts of ethyl iodide are then added during 15 minutes to the stirred solution. The mixture is heated under reflux for 45 minutes, and is then cooled to room temperature. A solution of 0.5 part of sodium in 40 parts of ethanol is added, followed by 3.9 parts of ethyl iodide, and the mixture is stirred and heated under reflux for 3 hours. 200 parts of water are added, and the mixture is concentrated under reduced pressure. The residue is extracted with 300 parts of ether, and the extract is dried and distilled. There is thus obtained 4'-Chl01'0oc ethyldesoxybenzoin, B.P. 122126 C./0.1 mm.

EXAMPLE 5 A mixture of 12.8 parts of 1-p-(2 dimethylaminoethyl)phenyl-1,2-di-p-chlorophenylbutan-l-ol, 400 parts of ethanol and 50 parts of concentrated hydrochloric acid is heated under reflux for 24 hours and then evaporated to dryness. The residue is crystallised once from a mixture of 40 parts of ethanol and 50 parts of concentrated hydrochloric acid, and then three times from ethanol. There is thus obtained 1-p-( 2-dimethylaminoethyl)phenyltrans-l,2-di-p-chlorophenylbut-l-ene hydrochloride, M.P. 251-253 C. (base, M.P. l13-l15 C.).

The 1-p-(2-dimethylaminoethyl)phenyl 1,2 di-p-chlorophenylbutan-l-ol, M.P. 156158 C., used as starting material may be obtained by repeating the process described in the second part of Example 1, except that that the a-ethyl desoxybenzoin is replaced by 4,4'-dichloroa-ethyldesoxybenzoin, B.P. 150-154 C./0.3 mm., which may be obtained by ethylation of 4,4-dichlorodesoxybenzoin using the procedure described in Example 4.

EXAMPLE 6 The process described in Example 5 is repeated except that the l-p-(Z-dimethylaminoethyl)phenyl-1,2-di-pchlorophenylbutan-l-ol is replaced by 1-p-(2-dimethylaminoethyl)phenyl-Z-p-chlorophenyl l p-tolylbutan-l- 01. There is thus obtained 1-p-(Z-dimethylaminoethyl) phenyl-trans-l-p-tolyl 2 p-chlorophenylbut-l-ene hydrochloride, M.P. 259-261 C.

The l-p-(2-dimethylaminoethyl)phenyl 2 p-chlorophenyl-l-p-tolylbutan-l-ol, M.P. 135-l37 C., used as starting material may be obtained by repeating the process described in the second part of Example 1 except that the 12.2 parts of a-ethyldesoxybenzoin is replaced by 13.5 parts of 4-chloro-a-ethyl-4-methyldesoxybenzoin.

In a similar manner by replacing the 13.5 parts of 4'-chloro-a-ethyl 4 methyldesoxybenzoin by 12.5 parts of a-ethyl-4,4'-dimethyldesoxybenzoin there is obtained a mixture of the hydrochlorides of the cis and trans isomers of l-p-(2-dimethylaminoethyl)phenyl 1,2 di-ptolylbut-l-ene, Which is crystallised from a mixture of ethanol and ethyl acetate and then converted to a mixture of the free bases. The bases are then recrystallised from petroleum ether (B.P. 4060 C.) and there is thus obtained the trans isomer, M.P. 108109 C. (hydrochloride, M.P. 274-276 C.).

The 4-chloro-u-ethyl 4 methyldesoxybenzoin, B.P. 150-152 C./0.4 mm., and the (it-ethyl 4,4 dimethyldesoxybenzoin, B.P. 140144 C./0.25 mm., are obtained by ethylation of 4'-chloro-4-methyldesoxybenzoin and 4,4- dimethyldesoxybenzoin respectively, by using the procedure described in Example 4.

4-chloro-4-methyldesoxybenzoin is prepared as follows:

To the Grignard reagent prepared in the usual manner from 14 parts of magnesium and 100 parts of p-bromotoluene in 300 parts of ether is added a solution of 29.6 parts of p-chlorobenzylcyanide in 150 parts of ether, and the mixture is heated under reflux for 16 hours. The cooled reaction mixture is poured on to a mixture of 800 parts of crushed ice and 150 parts of concentrated sulphuric acid, and is stirred for two hours. The organic layer (A) is separated, and the aqueous solution is heated at 90l00 C. for 1 hour and is then cooled and extracted with 1000 parts of ether. The extract is combined with the organic layer (A), dried, and evaporated. 4-chloro-4-methyldesoxybenzoin crystallises from the residual oil, and is recrystallised from ethanol. It melts at 11l1 12 C.

EXAMPLE 7 2.8 parts of N,N-dimethyl-3-(m-bromophenyl)propylamine and 40 parts of dry ether are stirred under nitrogen and 6 parts of a 15% W./v. solution of butyl lithium in hexane are added. The mixture is stirred for minutes, and then a solution of 2.6 parts of a-ethyldesoxybenzoin in parts of ether, is added. The mixture is then heated under reflux for 1 hour, and then cooled. The mixture is then poured into 100 parts of Water, the organic layer is separated, and the aqueous solution is extracted twice, each time with parts of chloroform. The extract and the organic layer are combined, dried over sodium sulphate, and evaporated, and the residual syrup is dissolved in 130 parts of chloroform. The chloroform solution is washed three times, each time with 50 parts of N-hydrochloric acid, then with 50 parts of aqueous sodium carbonate solution, and then dried and evaporated. The residue is dissolved in a mixture of parts of ethanol and 10 parts of concentrated hydrochloric acid, and the solution is heated under reflux for 24 hours and then concentrated. 200 parts of water are added, and the solution is made alkaline with sodium hydroxide solution and is extracted three times with parts of chloroform. The extract is dried and evaporated, and the residual syrup is dissolved in benzene and is purified by chromatography on alumina; non-basic impurities are first eluted with benzene, and the basic product is then eluted with ethanol. The base is converted into an oxalate by treatment with oxalic acid in ether-acetone, and by repeated crystallisation of the oxalate from ethanol there is obtained 1-m-(3-dimethylaminopro yl)phenyl-trans-1,2-diphenylbut-l-ene oxalate, M.P. -172 C.

The N,N-dimethyl 3 (m-bromophenyl)propylamine used as starting material may be prepared as follows:

25 parts of 3-bromoacetophenone, 13.25 parts of dimethylamine hydrochloride, 5 parts of paraformaldehyde, 20 parts of ethanol and 1 part of concentrated hydrochloric acid are stirred and heated under reflux for 4 hours. The solution is cooled, and fi-dimethylamino-3- bromopropiophenone hydrochloride, M.P. 205207 C. is filtered off and washed with acetone. 25 parts of this product are suspended in a mixture of 50 parts of water and 55 parts of concentrated hydrochloric acid, and the suspension is added to amalgamated zinc, prepared by shaking 50 parts of zinc W00], 5 parts of mercuric chloride, 100 parts of water and 3 parts of concentrated hydrochloric acid together for 15 minutes and then decanting the aqueous solution. The mixture is heated under reflux for 7 hours, and is then allowed to cool. The aqueous layer is decanted, and the zinc is thoroughly washed with water. The combined aqueous solutions are made strongly alkaline with sodium hydroxide, and are then extracted three times with 400 parts of ether. The extracts are dried and evaporated, and the residual oil is distilled. The frac- 9 tion of B.P. 130-140 C./ 8 mm. is further purified by vapour phase chromatography, and there is thus obtained N,N dimethyl-3-(m-bromophenyl) propylamine Which gives a picrate of M.P. 108109 C.

EXAMPLE 8 A mixture of 6.5 parts of l-p-(3-diethylaminopropyl) phenyl-l,2,-diphenylpropan-1-ol, 100 parts of ethanol and parts of concentrated hydrochloric acid is heated under reflux for 3 hours. The acid solution is evaporated, and the residual oil is triturated with ethyl acetate until it solidifies. The solid is collected and recrystallised from ethyl acetate. There is thus obtained 1-p-(3-diethylaminopropyl) phenyl-trans-1,2-dipheny1prop-l-ene hydrochloride, M.P. 167168 C.

The 1 p (3-diethylaminopropyl)phenyl-1,2-diphenylpropanol is prepared as follows:

5.25 parts of butyl lithium in 35 parts of hexane are added to 17.8 parts of N,N-diethyl-3-(p-bromophenyl) propylamine in 50 parts of ether. The mixture is stirred for 20 minutes, and then cooled to l5 C. A solution of 13.8 parts of a-methyldesoxybenzoin in 30 parts of ether is then added during 30 minutes at 20 C. to C. The mixture is allowed to attain ambient temperature, and stirred for 2 hours. The resulting solution is poured into 100 parts of water, and the ethereal phase is separated. The ethereal solution is extracted with 100 parts of N-acetic acid, and the acidic extract is made strongly alkaline with sodium hydroxide solution. The liberated base is extracted with ether and the extract is dried and evaporated. The residue is crystallised from petroleum ether (B.P. 60-80" C.) and there is thus obtained 1-p-(3-diethylaminopropyl)phenyl-1,2-diphenylpropan-l-ol, M.P. 92-94 C.

In a similar manner, by replacing the a-methyldesoxybenzoin by u-ethyldesoxybenzoin, there is thus obtained 1-p-(3-diethylaminopropyl)phenyl-trans 1,2 diphenylbut-l-ene hydrochloride, M.P. 182l83 C. (crystallised from acetone).

In a similar manner, by replacing the N,N-diethyl-3- (p-bromophenyl)propylamine in the last mentioned process by N,N dimethyl-3-(p-bromophenyl)-propylarnine, there is thus obtained 1-p-(3-dimethylaminopropyl) phenyl trans-1,2-diphenylbut-l-ene hydrochloride, M.P. 166167 C. (crystallised from ethyl acetate), and the corresponding cis isomer hydrochloride, M.P. 199201 C. (crystallised from acetone).

The N,N-dimethyl-3-(p-bromophenyl)propylamine is obtained as follows:

A mixture of 55.6 parts of 3-(p-bromophenyl)-propylbromide, 36 parts of dimethylamine and 250 parts of ethanol is heated in an autoclave at 60 C. for 24 hours. The mixture is cooled, the solvent evaporated, and the residue stirred with 2 N-sodium hydroxide. The alkaline mixture is extracted With ether, and the ethereal extract is re-extracted With 2 N-hydrochloric acid solution. The acidic extract is made alkaline with 10 N-sodium hydroxide solution, and again extracted with ether. The extract is dried and evaporated, and the residue is distilled. There is thus obtained N,N-dimethyl-3-(p-bromophenyl)- propylamine, B.P. 90-93" C./0.15 mm.

EXAMPLE 9 50 parts of l-p-(2-dimethylaminoethyl)phenyl-trans-2 p-chlorophenyl-l-phenylbut-l-ene hydrochloride, 42 parts of maize starch and 7 parts of alginic acid are intimately mixed and granulated using 10% maize starch paste as the granulating agent. The granules are dried at a temperature not exceeding 50 C., then mixed with 1 part of magnesium stearate and compressed into tablets each weighing 50 mg. There are thus obtained tablets suitable for oral administration for therapeutic purposes.

What we claim is:

1. A trans isomer of an alkene derivative selected from the group consisting of compounds of the formula:

wherein R and R are alkyl of 1-2 carbon atoms, A is alkylene of up to 4 carbon atoms, R and R are selected from the group consisting of phenyl, halophenyl, methylphenyl and methoxy phenyl, and R is alkyl of 1-4 carbon atoms and the pharmaceutically-acceptable salts thereof.

2. A compound according to claim 1 which is the trans isomer of l-p-(Z-dimethylaminoethyl)phenyl-1,2-di phenylbut-l-ene.

3. A compound according to claim 1 which is the trans isomer of l-p-(Z-dimethylaminoethyl)-phenyl-1-pmethoxyphenyl-2-phenylbut-l-ene.

4. A compound according to claim 1 which is the trans isomer of 1p-(2-dimethylaminoethyl)phenyl-2- phenyl-l-p-tolylbut-l-ene.

5. A compound according to claim 1 which is the trans isomer of 1-p-(2-dimethylaminoethyl)phenyl-2-p-chlorophenyl-1-phenylbut1-ene.

6. A compound according to claim 1 which is the trans isomer of l-p-(2-dimethylaminoethyl)phenyl-1,2-dip-chlorophenylbut-l-ene.

7. A compound according to claim 1 which is the trans isomer of l-p-(Z-dimethylaminoethyl)phenyl-l-ptolyl-2-p-chlorophenylbut-1-ene.

8. A compound according to claim 1 which is the trans isomer of l-p-(Z-dimethylaminoethyl)phenyl-1,2-dip-tolylbut-1-ene.

9. A compound according to claim 1 which is the trans isomer of 1-p-(3-dimethylaminopropyl)phenyl1,2- di-phenylbut-l-ene.

10. A compound according to claim 1 which is the trans isomer of l-p-(3-diethylaminopropyl)-phenyl-1,2-diphenylbut-l-ene.

11. A compound according to claim 1 which is the trans isomer of 1-p(3-diethylaminopropyl)phenyl-1,2-diphenylprop-l-ene.

References Cited UNITED STATES PATENTS 4/1966 Palopoli et al 260570 X 9/1967 Richardson 260-570 X ROBERT V. HINES, Primary Examiner U.S. Cl. X.R. 

